Effects of rapamycin and deferoxamin on wound healing after ischemia and hypoxia_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

 NIE Kaiyu , HU Peng , WANG Dali , WEI Zairong , ZENG Xueqin , SUN Guangfeng

Department of Burns and Plastic Surgery, the Affiliated Hospital of Zunyi Medical College, Zunyi Guizhou, 563000, P.R.China;

Corresponding author：

NIE Kaiyu, Email: niekaiyu@yahoo.com.cn

Keywords：

Rapamycin; deferoxamin; mammalian target of rapamycin; hypoxia inducible factor 1α; wound healing

DOI：

10.7507/1002-1892.201608081

Video：

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Objective To explore the effect and mechanism of rapamycin and deferoxamin on wound healing after ischemia and hypoxia. Methods The model of ischemia and hypoxia wound was made on the back of 40 SPF male adult Sprague Dawley rats, weight (300±20) g; they were randomly divided into 4 groups (n=10): the control group (group A), deferoxamine intervention group (group B), rapamycin intervention group (group C), and deferoxamine+rapamycin intervention group (group D). At 3, 6, and 9 days after model preparation, rats of groups A, B, C, and D were intra-peritoneally injected with normal saline, deferoxamin (10 mg/kg), rapamycin (3 mg/kg), deferoxamin (10 mg/kg)+rapamycin (3 mg/kg) respectively. The wound healing was observed and the healing time was recorded in each group; the wound healing tissue was harvested to test the mRNA and protein expressions of mammalian target of rapamycin (mTOR), hypoxia inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) by real-time fluorescence quantitative PCR and Western blot at 2 days after wound healing. Results All rats survived to the end of the experiment, and wounds healed; the healing time of groups A, B, and D was significantly shorter than that of group C (P<0.05), but there was no significant difference between groups A, B, and D (P>0.05). Real-time fluorescence quantitative PCR showed that the expression of mTOR mRNA in groups C and D was significantly decreased when compared with the expressions in groups A and B (P<0.05); there was significant difference between groups A and B (P<0.05), but no significant difference between groups C and D (P>0.05). The expressions of HIF-1α mRNA and VEGF mRNA were signi-ficantly higher in groups B and D than groups A and C, and in group A than group C (P<0.05), but there was no signifi-cant difference between groups B and D (P>0.05). Western blot showed that the relative expressions of mTOR protein in groups C and D were significantly decreased when compared with the expressions in groups A and B (P<0.05), but there was no significant difference between groups C and D (P>0.05). The relative expressions of HIF-1α protein in groups A, B, and C were significantly increased when compared with expression in group D (P<0.05), but there was no significant difference between groups A, B, and C (P>0.05). The relative expression of VEGF protein were significantly lower in groups B, C, and D than group A, in group D than groups B and C, and in group C than group B (P<0.05). Conclusion Defe-roxamin can promote the wound healing of rats after ischemia and hypoxia, and the effect of rapamycin is opposite. It may be related to the existence of mTOR and HIF-1 signaling pathway in chronic ischemia-hypoxia wound.

Citation： NIE Kaiyu, HU Peng, WANG Dali, WEI Zairong, ZENG Xueqin, SUN Guangfeng. Effects of rapamycin and deferoxamin on wound healing after ischemia and hypoxia. Chinese Journal of Reparative and Reconstructive Surgery, 2017, 31(6): 718-722. doi: 10.7507/1002-1892.201608081 Copy

1.	唐彬轶, 屈艺, 母得志. 缺氧诱导因子 1α 在缺氧缺血性损伤中的研究进展. 中国修复重建外科杂志, 2009, 23(6): 755-757.
2.	张丹, 任利玲. 缺氧诱导因子 1α 在组织工程成骨和成血管中的作用. 中国修复重建外科杂志, 2016, 30(4): 504-506.
3.	Thackham JA, McElwain DL, Long RJ. The use of hyperbaric oxygen therapy to treat chronic wounds: A review. Wound Repair Regen, 2008, 16(3): 321-330.
4.	聂开瑜, 李鹏程. bFGF 联合局部氧疗促进烧伤创面愈合的临床观察. 中国修复重建外科杂志, 2010, 24(6): 643-646.
5.	Botusan IR, Sunkari VG, Savu O, et al. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A, 2008, 105(49): 19426-19431.
6.	Thangarajah H, Vial IN, Grogan RH, et al. HIF-1alpha dysfunction in diabetes. Cell Cycle, 2010, 9(1): 75-79.
7.	Thangarajah H, Yao D, Chang EI, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A, 2009, 106(32): 13505-13510.
8.	Chang EI, Loh SA, Ceradini DJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation, 2007, 116(24): 2818-2829.
9.	Liu L, Marti GP, Wei X, et al. Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol, 2008, 217(2): 319-327.
10.	Loh SA, Chang EI, Galvez MG, et al. SDF-1 alpha expression during wound healing in the aged is HIF dependent. Plast Reconstr Surg, 2009, 123(2 Suppl): 65S-75S.
11.	Hoenig MR, Bianchi C, Rosenzweig A, et al. Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1. Curr Mol Med, 2008, 8(8): 754-767.
12.	Schwacha MG, Nickel E, Daniel T. Burn injury-induced alterations in wound inflammation and healing are associated with suppressed hypoxia inducible factor-1alpha expression. Mol Med, 2008, 14(9-10): 628-633.
13.	Koh MY, Spivak-Kroizman TR, Powis G. HIF-1alpha and cancer therapy. Recent Results Cancer Res, 2010, 180: 15-34.
14.	Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1 expression and function by the mammalian target of rapamycin. Mol Cell Biol, 2002, 22(20): 7004-7014.
15.	Ma D, Lim T, Xu J, et al. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol, 2009, 20(4): 713-720.
16.	程剑, 张蕾. 缺氧诱导因子 1α 参与异氟醚延迟性预处理减轻小鼠肾脏缺血再灌注损伤的研究. 中国修复重建外科杂志, 2010, 24(4): 477-480.
17.	Chen C, Schultz GS, Bloch M, et al. Molecular and mechanistic validation of delayed healing rat wounds as a model for human chronic wounds. Wound Repair Regen, 1999, 7(6): 486-494.
18.	Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications withde novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant, 2006, 6(5 Pt 1): 986-992.
19.	Schäffer M, Schier R, Napirei M, et al. Sirolimus impairs wound healing. Langenbecks Arch Surg, 2007, 392(3): 297-303.
20.	Singh KP, Prasad R, Chari PS, et al. Effect of growth hormone therapy in burn patients on conservative treatment. Burns, 1998, 24(8): 733-738.
21.	付小兵. 进一步重视体表慢性难愈合创面发生机制与防治研究. 中华创伤杂志, 2004, 20(8): 449-451.

1. 唐彬轶, 屈艺, 母得志. 缺氧诱导因子 1α 在缺氧缺血性损伤中的研究进展. 中国修复重建外科杂志, 2009, 23(6): 755-757.
2. 张丹, 任利玲. 缺氧诱导因子 1α 在组织工程成骨和成血管中的作用. 中国修复重建外科杂志, 2016, 30(4): 504-506.
3. Thackham JA, McElwain DL, Long RJ. The use of hyperbaric oxygen therapy to treat chronic wounds: A review. Wound Repair Regen, 2008, 16(3): 321-330.
4. 聂开瑜, 李鹏程. bFGF 联合局部氧疗促进烧伤创面愈合的临床观察. 中国修复重建外科杂志, 2010, 24(6): 643-646.
5. Botusan IR, Sunkari VG, Savu O, et al. Stabilization of HIF-1alpha is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A, 2008, 105(49): 19426-19431.
6. Thangarajah H, Vial IN, Grogan RH, et al. HIF-1alpha dysfunction in diabetes. Cell Cycle, 2010, 9(1): 75-79.
7. Thangarajah H, Yao D, Chang EI, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues. Proc Natl Acad Sci U S A, 2009, 106(32): 13505-13510.
8. Chang EI, Loh SA, Ceradini DJ, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation, 2007, 116(24): 2818-2829.
9. Liu L, Marti GP, Wei X, et al. Age-dependent impairment of HIF-1alpha expression in diabetic mice: Correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J Cell Physiol, 2008, 217(2): 319-327.
10. Loh SA, Chang EI, Galvez MG, et al. SDF-1 alpha expression during wound healing in the aged is HIF dependent. Plast Reconstr Surg, 2009, 123(2 Suppl): 65S-75S.
11. Hoenig MR, Bianchi C, Rosenzweig A, et al. Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1. Curr Mol Med, 2008, 8(8): 754-767.
12. Schwacha MG, Nickel E, Daniel T. Burn injury-induced alterations in wound inflammation and healing are associated with suppressed hypoxia inducible factor-1alpha expression. Mol Med, 2008, 14(9-10): 628-633.
13. Koh MY, Spivak-Kroizman TR, Powis G. HIF-1alpha and cancer therapy. Recent Results Cancer Res, 2010, 180: 15-34.
14. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1 expression and function by the mammalian target of rapamycin. Mol Cell Biol, 2002, 22(20): 7004-7014.
15. Ma D, Lim T, Xu J, et al. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol, 2009, 20(4): 713-720.
16. 程剑, 张蕾. 缺氧诱导因子 1α 参与异氟醚延迟性预处理减轻小鼠肾脏缺血再灌注损伤的研究. 中国修复重建外科杂志, 2010, 24(4): 477-480.
17. Chen C, Schultz GS, Bloch M, et al. Molecular and mechanistic validation of delayed healing rat wounds as a model for human chronic wounds. Wound Repair Regen, 1999, 7(6): 486-494.
18. Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications withde novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant, 2006, 6(5 Pt 1): 986-992.
19. Schäffer M, Schier R, Napirei M, et al. Sirolimus impairs wound healing. Langenbecks Arch Surg, 2007, 392(3): 297-303.
20. Singh KP, Prasad R, Chari PS, et al. Effect of growth hormone therapy in burn patients on conservative treatment. Burns, 1998, 24(8): 733-738.
21. 付小兵. 进一步重视体表慢性难愈合创面发生机制与防治研究. 中华创伤杂志, 2004, 20(8): 449-451.

Chinese Journal of Reparative and Reconstructive Surgery

Effects of rapamycin and deferoxamin on wound healing after ischemia and hypoxia

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